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J Clin Endocrinol Metab. 2019 Dec 1;104(12):6256-6264. doi: 10.1210/jc.2019-00762.

PLIN2 Functions As a Novel Link Between Progesterone Signaling and Metabolism in Uterine Leiomyoma Cells.

Author information

1
Division of Reproductive Science in Medicine, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
2
Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

Abstract

CONTEXT:

Uterine leiomyoma (fibroids) are the most common tumors in women. Recently, perilipin-2 (PLIN2) was identified as a critical target gene of the progesterone receptor; however, its function in the pathogenesis of fibroids is unknown.

OBJECTIVE:

To determine the function of PLIN2 in leiomyoma cells.

DESIGN:

Tissue and primary cells from leiomyoma and myometrium were analyzed. PLIN2 function in leiomyoma was assessed using small interfering RNA. RNA-sequencing was performed to identify genome-wide effects of PLIN2 depletion. Metabolic activity was measured using the Seahorse XF96 analyzer. Real-time quantitative PCR and immunoblotting were also performed.

SETTING:

Laboratory.

PATIENTS OR OTHER PARTICIPANTS:

Forty-one premenopausal women undergoing surgery for fibroids.

MAIN OUTCOME MEASURES:

Gene expression, oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and cell proliferation.

RESULTS:

PLIN2 gene expression was 2.4-fold lower in leiomyoma compared with adjacent myometrium, suggesting a link between PLIN2 deficiency and fibroids. A total of 3877 genes were differentially expressed after PLIN2 knockdown. Gene ontology analysis identified metabolism as the second-highest biological process affected by PLIN2 depletion. OCR (mitochondrial respiration) and ECAR (glycolysis) were significantly upregulated after PLIN2 knockdown; PLIN2-depleted cells had a greater basal metabolic activity and higher metabolic stress response. Cell proliferation was also significantly increased after PLIN2 knockdown.

CONCLUSIONS:

PLIN2 depletion increases mitochondrial respiration and glycolysis, suggesting that PLIN2 is a critical regulator of metabolic function in leiomyoma cells. PLIN2 deficiency also reprograms leiomyoma cells to a proproliferative phenotype. These findings introduce metabolomics as an area to explore to better understand leiomyoma tumorigenesis.

PMID:
31504629
PMCID:
PMC6823729
[Available on 2020-07-23]
DOI:
10.1210/jc.2019-00762

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